Derivatization of Dihydropyrrolidone-Thiadiazole Heterocyclic Compounds and an Evaluation of their Antibacterial and Anti-Biofilm Activities

Abstract

A series of Dihydropyrrolidone-Thiadiazole inhibitors targeting YycG histidine kinase were designed and synthesized and evaluated for antibacterial, bactericidal, anti-biofilm, cytotoxicity, hemolytic activities and autophosphorylation. Compound 3i exhibited the best bacteriostatic activity against gram-positive bacteria such as S. epidermidis SE1457, MSSA SA113, and E. faecalis FB1 (MIC=3.13-25 μM). Its antibacterial activity against Methicillin-sensitive Staphylococcus aureus (MSSA) SA113 was comparable to that of linezolid. Most of the compounds had good inhibitory effects on the biofilms of the tested strains. Among them, compound 3a, compound 3n, and compound 3p showed strong inhibitory effects on the biofilm formation of S. epidermidis SE1457, MSSA SA113, and E. faecalis FB1, and their inhibition rates reached more than 90% at 6.25 μM, respectively. Cytotoxicity and hemolytic activity tests suggested all the compounds synthesized had little effect on the growth of mammalian cells (Vero cells) and have no hemolytic activity on healthy human red blood cells.